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Manuscript to be reviewed
Risk and clinical predictors of osteoporotic fracture in East

Asian patients with chronic obstructive pulmonary disease: a
population-based cohort study
Ping-Hsueh Lee 1, 2 , Victor C Kok Corresp.,
Tzong Horng Corresp. 4, 5, 6
1
2
3
4
5
6
7
3, 4, 5
, Po-Liang Chou
, Ming-Chang Ku
2, 7
, Yu-Ching Chen
4, 5
, Jorng-
Department of Geriatric Medicine, Kuang Tien General Hospital, Taichung, Taiwan

Jen-Te Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan
KTGH Cancer Center, Kuang Tien General Hospital, Taichung, Taiwan
Department of Bioinformatics and Medical Engineering, Asia University Taiwan, Taichung, Taiwan
Disease Informatics Research Group, Asia University Taiwan, Taiwan
Department of Computer Science and Information Engineering, National Central University, Jhongli, Taoyuan, Taiwan
Department of Diagnostic Radiology, Kuang Tien General Hospital, Taichung, Taiwan
Corresponding Authors: Victor C Kok, Jorng-Tzong Horng

Email address: victorkok@asia.edu.tw, horng@db.csie.ncu.edu.tw
Introduction: Osteoporosis is becoming an impending epidemic in the Asia-Pacific region. The

association between risk of osteoporotic fracture (OTPF) and chronic obstructive pulmonary disease
(COPD) in East Asian patients is yet to be fully examined. We conducted a nationwide population-based
retrospective cohort study of 98,700 patients aged 50 years with or without COPD using a national
administrative claims dataset.
Materials and Methods: The patients were divided into COPD and comparison groups comprising
19,740 and 78,960 patients, respectively. The groups were 1 to 4 matched for age, gender, index date,
diabetes mellitus, pre-existing osteoporosis and chronic kidney disease. Information such as the
geographic area where southern part represented more sunshine exposure, smoking-related diagnoses,
alcohol use disorder, whether there was regular use of inhaled corticosteroids and oral corticosteroids,
vitamin D prescriptions, Charlson-Deyo comorbidity index score, and other relevant medical
comorbidities were extracted for analysis. They were followed up until OTPF or the end of the year 2013.
The outcome measure was an osteoporotic vertebral fracture and other long-bone fractures. A
multivariate Cox model was constructed to derive adjusted hazard ratios (aHR) for OTPF with
corresponding 95% confidence intervals (CI) after controlling for age, sex, insurance premium category,
vitamin D prescription, osteoporosis, and coronary heart disease (CHD). KaplanMeier curves of the
probability of OTPF-free survival for each cohort were compared using the log-rank test. Patients with
OTPF during the first follow-up year were excluded from the overall risk calculation. Contributing factors
to the increased risk of OTPF in COPD patients were examined in a sensitivity analysis.
Results: After a total follow-up of 68,743 patient-years for the COPD group and 278,051 patient-years
for the matched comparison group, the HR for OTPF was 1.24 (95% CI, 1.021.51; P = 0.0322) in COPD
patients. The aHR was increased by 30% for vertebral OTPF (aHR = 1.297, 95% CI 1.0201.649; P =
0.0339). Differential lag time sensitivity analysis revealed a progressively elevated risk up to 8-fold
increase in women (aHR = 8.0 (95% CI, 1.8135.4; P < 0.01) during the fifth follow-up year. COPD
patients with pre-existing osteoporosis or given vitamin D prescription harbor a sustained increased risk
up to the 5th (aHR, 4.1; 95% CI, 1.6110.35) and third (aHR, 2.97; 95% CI, 1.485.97) follow-up year,
PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)
respectively.
Conclusions: Our nationwide population-based cohort study demonstrates that East Asian COPD
patients aged 50 and beyond do harbor a modestly increased risk for osteoporotic vertebral fractures
particularly who are female, have pre-existing osteoporosis or require vitamin D prescription.
1
Risk and clinical predictors of osteoporotic fracture in East Asian
patients with chronic obstructive pulmonary disease: a population-
based cohort study
4
5
Short Title: Osteoporotic fracture in Asians with COPD
6
7
Ping-Hsueh Lee1, 2, MD; Victor C. Kok3, 4, 5, *, MD, PhD, FACP; Po-Liang Chou6, BSc; Ming-
Chang Ku2, 7, MD; Yu-Ching Chen3, 5, PhD; Jorng-Tzong Horng3, 5, 6, *, PhD.
9
10
1Department
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2Jen-Te
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3Disease
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of Internal Medicine, Kuang Tien General Hospital, Taichung, Taiwan
14
5Department
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Taiwan
16
6Department
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Jhongli, Taiwan
18
7Department
of Geriatric Medicine, Kuang Tien General Hospital, Taichung, Taiwan
Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan

Informatics Research Group, Asia University Taiwan, Taichung, Taiwan 4Department
of Bioinformatics and Medical Engineering, Asia University Taiwan, Taichung,
of Computer Science and Information Engineering, National Central University,
of Radiology, Kuang Tien General Hospital, Taichung, Taiwan.
19
20
*Corresponding authors:
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Victor C. Kok, MMedSc, MD, PhD, FACP
22
Kuang Tien General Hospital
23
117 Shatien Road Shalu, Taichung 43303, Taiwan
24
Tel: +886 4 26625111, ext: 2263
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Fax: +886 4 26655050
26
E-mail: victorkok@asia.edu.tw
27
28
Jorng-Tzong Horng, PhD
29
Department of Computer Science and Information Engineering
30
National Central University
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300 Jhongda Road, Jhongli, Taoyuan 32001, Taiwan
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Tel +886 919 057 555
33
E-mail: horng@db.csie.ncu.edu.tw
34
35
Tables: 4 (including one supplement table)
36
Figures: 4 (including one supplement figure)
37
Word count of the main manuscript: 3717
38
Abstract word count: 413
39
Abstract
40
41
Introduction: Osteoporosis is becoming an impending epidemic in the Asia-Pacific region. The
42
association between risk of osteoporotic fracture (OTPF) and chronic obstructive pulmonary
43
disease (COPD) in East Asian patients is yet to be fully examined.
44
We conducted a nationwide population-based retrospective cohort study of 98,700 patients aged
45
50 years with or without COPD using a national administrative claims dataset.
46
Materials and Methods: The patients were divided into COPD and comparison groups
47
comprising 19,740 and 78,960 patients, respectively. The groups were 1 to 4 matched for age,
48
gender, index date, diabetes mellitus, pre-existing osteoporosis and chronic kidney disease.
49
Information such as the geographic area where southern part represented more sunshine
50
exposure, smoking-related diagnoses, alcohol use disorder, whether there was regular use of
51
inhaled corticosteroids and oral corticosteroids, vitamin D prescriptions, Charlson-Deyo
52
comorbidity index score, and other relevant medical comorbidities were extracted for analysis.
53
They were followed up until OTPF or the end of the year 2013. The outcome measure was an
54
osteoporotic vertebral fracture and other long-bone fractures. A multivariate Cox model was
55
constructed to derive adjusted hazard ratios (aHR) for OTPF with corresponding 95% confidence
56
intervals (CI) after controlling for age, sex, insurance premium category, vitamin D prescription,
57
osteoporosis, and coronary heart disease (CHD). KaplanMeier curves of the probability of
58
OTPF-free survival for each cohort were compared using the log-rank test. Patients with OTPF
59
during the first follow-up year were excluded from the overall risk calculation. Contributing
60
factors to the increased risk of OTPF in COPD patients were examined in a sensitivity analysis.
61
Results: After a total follow-up of 68,743 patient-years for the COPD group and 278,051
62
patient-years for the matched comparison group, the HR for OTPF was 1.24 (95% CI, 1.021.51;
63
P = 0.0322) in COPD patients. The aHR was increased by 30% for vertebral OTPF (aHR =
64
1.297, 95% CI 1.0201.649; P = 0.0339). Differential lag time sensitivity analysis revealed a
65
progressively elevated risk up to 8-fold increase in women (aHR = 8.0 (95% CI, 1.8135.4; P <
66
0.01) during the fifth follow-up year. COPD patients with pre-existing osteoporosis or given
67
vitamin D prescription harbor a sustained increased risk up to the 5th (aHR, 4.1; 95% CI, 1.61
68
10.35) and third (aHR, 2.97; 95% CI, 1.485.97) follow-up year, respectively.
69
Conclusions: Our nationwide population-based cohort study demonstrates that East Asian
70
COPD patients aged 50 and beyond do harbor a modestly increased risk for osteoporotic
71
vertebral fractures particularly who are female, have pre-existing osteoporosis or require vitamin
72
D prescription.
73
(Word count: 413)
74
75
Keywords: COPD, osteoporotic fracture, Asian, longitudinal study, osteoporosis
76
77
78
Introduction
Osteoporosis is the most common bone disease in the world and is characterized by low
79
bone mass and derangement of bone microarchitecture. The prevalence of osteoporotic fracture
80
(OTPF) was estimated to be 9.0 million worldwide in the year 2000 (Johnell & Kanis 2006). In a
81
cohort of Chinese women, the prevalence rates of primary osteoporosis affecting the spine,
82
femoral neck, and hip were reported to be 32%34%, 16.3%, and 18.9%, respectively (Wu et al.
83
2004). In other Asian countries, the prevalence rate of osteoporosis in women 50 years has been
84
reported as 34% in Korea and 31% in Japan (Choi et al. 2012; Iki et al. 2001). OTPF results in
85
significant reductions in quality of life due to pain, depression, and disability (Poole & Compston
86
2006). Elderly patients who sustain nondisplaced hip fractures experience predictable and lasting
87
loss of function, particularly in patients with pulmonary disease. Both age and chronic
88
obstructive pulmonary disease (COPD) affect the speed of functional recovery (Eisler et al.
89
2002). Furthermore, the mortality rate following hip fracture reportedly was as high as 36% in a
90
systemic epidemiological review (Abrahamsen et al. 2009). The estimated cost of treatment of
91
osteoporosis-related fracture in the United States was approximately $17 billion in 2005 and is
92
estimated to increase to $25.3 billion by 2025 (Burge et al. 2007).
93
Despite the substantial clinical burden of osteoporosis, treatment rates are low in some East
94
Asian countries. In a national screening program in Korea, the estimated treatment rate was only
95
14.4% in osteoporotic women (Choi et al. 2012). Because low bone mineral density (BMD) is a
96
major risk factor for fractures, timely treatment can prevent this disastrous outcome (Nelson et
97
al. 2010). Therefore, early identification of high-risk patients is an important step toward
98
increasing treatment rates. However, relying on BMD screening alone is not considered
99
sufficient to detect high-risk patients in a timely and cost-effective manner (Ogura-Tomomatsu et
100
101
al. 2012; Schuit et al. 2004).

Patients with COPD have many shared features with osteoporotic patients, such as low body
102
mass index (BMI), inactivity, and chronic steroid use. COPD has been shown to be associated
103
with low BMD in recent studies (Jaramillo et al. 2015; Looker 2014). However, the association
104
between risk of OTPF and COPD has not been well studied, particularly in the Asian population.
105
The prevalence of osteoporosis has been shown to be higher in COPD patients compared with
106
controls (Graat-Verboom et al. 2009; Schnell et al. 2012), and the prevalence of hip fracture was
107
reportedly higher in a cross-sectional study of 465 COPD patients in Brazil (Kulak et al. 2010).
108
To date, no studies have been reported from East Asian countries regarding the magnitude of the
109
risk of subsequent OTPF contributed by each clinical predictor in COPD patients. The aim of the
110
present study was to evaluate the association between COPD and risk of OTPF and identify
111
clinical predictors of fracture in East Asian patients. The magnitude of the risk of OTPF
112
contributed by clinical predictors would be calculated.
113
114
Materials and Methods
115
Data source
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Data from 2007 to 2013 was obtained from the Longitudinal Health Insurance Dataset
117
(LHID) of the National Health Insurance Research Database (NHIRD). The National Health
118
Insurance (NHI) program, established in 1995 in Taiwan, is a mandatory health insurance
119
program requiring every resident, from a newborn to an elderly person, to join. It provides
120
comprehensive insurance coverage for medical services through outpatients, inpatients, and
121
emergency departments, in addition to traditional Chinese medicine. The program currently has a
122
coverage rate of 99%. LHID consists of 1 million beneficiaries randomly sampled from NHIRD.
123
The dataset includes NHI enrolment files and claims data, such as examinations, medical
124
procedures, drug prescriptions, and diagnoses, of all included patients. The International
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Classification of Diseases, Ninth Revision, Clinical Modification codes (ICD-9-CM codes; 2001
126
revision) were used by physicians to code diseases in the system. All recognizable personal
127
information was encrypted according to regulations specified by the Bureau of NHI. The authors
128
have successfully conducted several population-based retrospective cohort studies using the
129
LHID (Kok et al. 2014; Kok et al. 2016; Kok et al. 2015a; Kok et al. 2015b). The present study
130
was approved by the accredited local in-house Institutional Review Board with a certificate
131
number KTGH-IRB 10520. The IRB approved that no any form of consent (Verbal / Written)
132
was required for this study.
133
134
Study Design
135
We conducted a population-based, observational, cohort study to assess the association
136
between COPD and risk of OTPF. All patients diagnosed with COPD between January 2007 and
137
December 2013 were identified (ICD-9 CM: 490492, 496). The index date was defined as the
138
month in which the diagnosis of COPD was made. Exclusion criteria were as follows: (1) age
139
<50 years; (2) less than two COPD outpatient claims within 1 year with no inpatient records; and
140
(3) pre-existing COPD or OTPF before January 1, 2007. The control group was composed of the
141
remaining patients in LHID without COPD, with 1 to 4 matched for age, gender, and index
142
month, diabetes mellitus, pre-existing osteoporosis and chronic kidney disease. The exclusion
143
criteria applied to the COPD group was used for the control group. All study patients were
144
followed up until the first incidence of OTPF which was further separated into vertebral fractures
145
and the other long bone fractures, drop-out from the insurance program, or the end of the present
146
study.
147
148
Data extraction
149
Patients age, gender, date of accrual, geographic residential area, insurance premium
150
category, behavioral proxies such as smoking related diagnoses and alcohol use disorders;
151
medical comorbidities including diabetes mellitus, pre-existing osteoporosis, chronic kidney
152
disease, rheumatoid arthritis, hypertension, dyslipidemia, coronary heart disease, chronic liver
153
disease, stroke and dementia; medical prescriptions such as vitamin D, inhaled corticosteroids
154
(ICS: budesonide, beclomethasone, ciclesonide, fluticasone) and oral corticosteroids (OCS:
155
cortisone acetate, dexamethasone, fludrocortisone, methylprednisolone, prednisolone,
156
triamcinolone); and Charlson-Deyo Comorbidity Index Score were collected from the dataset
157
and calculated. Longitudinal tracking data of study participants until the occurrence of a specific
158
type of osteoporotic fracture, e.g., vertebral fracture or femoral neck fracture were extracted.
159
Candidates who would be included were also screened for pathological fractures due to cancer
160
metastases (ICD-9-CM code 198.5), renal osteodystrophy (588.0) and secondary
161
hyperthyroidism (588.81).
162
163
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Outcome measures
The primary outcome measure of the present study was OTPF, defined as any pathological
165
fracture due to osteoporosis (ICD-9-CM codes: 733.0x + 733.1x) documented in inpatient or
166
outpatient data files during the study period. Osteoporotic vertebral fracture has a unique code as
167
733.13. To prevent overstated or false claiming, NHI randomly and regularly reviews claims
168
data, including patient history and laboratory and imaging reports. Only cases with correct
169
coding for all diagnoses are eligible for full reimbursement. Any violation of the coding
170
regulations results in payment retrieval plus a punitive fine, which may be several times the
171
original payment. To ensure accuracy, all coding procedures were performed by groups of
172
specialists assigned by contributing hospitals. OTPF in the present study was defined as any new
173
and matched ICD-9 coding of cohort subjects between 2007 and 2013 in outpatient, emergent, or
174
inpatient settings. Therefore, we believe that all events that occurred during the follow-up period
175
were recorded with a high degree of accuracy. Furthermore, we excluded pathological fractures
176
that resulted from cancer metastasis, renal osteodystrophy, or secondary hyperparathyroidism
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[ICD-9-CM codes: 733.1 + (198.5,588.0, or 588.1)] (Supplement Table 1). Patients with OTPF
178
during the first follow-up year were excluded from the overall risk calculation.
179
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Covariates and confounders
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Socioeconomic status of participating subjects was approximated using different category
182
by insurance premium. Exposure to different levels of sunshine was also taken into account by
183
the use of the residential area of the participating subjects (more sunshine in the southern part of
184
the country). Lifestyle factors included smoking-related diagnoses and alcohol used disorder
185
were used as proxies for cigarette smoking and alcohol drinking were extracted. Medication
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history of inhaled corticosteroid and/or oral corticosteroid use and vitamin D prescription were
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extracted from the dataset. Comorbidities were identified according to ICD-9-CM codes,
188
including rheumatoid arthritis, hypertension, dyslipidemia, coronary heart disease (CHD), liver
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disease, stroke, and dementia. An overall score of the Charlson-Deyo comorbidity index of each
190
patient was collected.
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Statistical analysis
Patient-year data and incidence rates were evaluated. A multivariate Cox model was
194
constructed to derive adjusted hazard ratios (aHR) with corresponding 95% confidence intervals
195
(CI) after controlling for factors that were revealed significant in the univariate Cox model so
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that overadjustment (overfitting) and noise could be avoided. Fracture-free survival was assessed
197
using the KaplanMeier analysis. Survival curves were compared between COPD and non-
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COPD groups using the log-rank test. Differential lag time sensitivity analysis was carried out to
199
examine the effect of different exposure time lag on the risk of osteoporotic fractures among
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COPD patients who possessed the characteristic such as female and specific medical
201
comorbidity. We used the bivariate Cox model to evaluate the risk of OTPF in COPD when
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coupled with each medical comorbidity. P-values of <0.05 were considered statistically
203
significant. All study analyses were performed using the SPSS statistical software (IBM SPSS
204
Statistics Version 22).
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Results
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Characteristics of the study population
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From 2007 to 2013, 92,656 newly-diagnosed COPD patients were identified from LHID (n
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= 965,659). Among these, 70,191 were excluded after applying the exclusion criteria described
210
above. Reasons for exclusion were as follows: incomplete data registration (n = 1,310) and
211
unsuccessful matching (n = 5,635). As a result, 19,740 patients were recruited to the COPD sub-
212
cohort and 78,960 to the non-COPD sub-cohort after 1 to 4 matching for age, gender, index
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month, diabetes mellitus, pre-existing osteoporosis and chronic kidney disease. The mean age
214
(and standard deviation) in the COPD group was 66 years (10.23), with 62.5% of patients <70
215
years of age. COPD patients were predominantly male (55.8%). The mean follow-up duration
216
was 2.97 years (standard deviation (SD), 2.06 years) in the COPD group and 3.01 years (SD,
217
2.05 years) in the non-COPD group, which were not statistically significantly different (P =
218
0.0949). Hypertension and hyperlipidemia were the most commonly observed co-morbidities.
219
Except for dyslipidemia, all non-matching co-morbidities, such as rheumatoid arthritis,
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hypertension, and coronary heart disease, were differently distributed between the two groups.
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The mean Charlson Comorbidity Index (CCI) score was significantly higher in the COPD sub-
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cohort (1.14 vs. 1.02; P < 0.0001; Table 1). More patients with COPD were classified as a
223
regular user of oral prednisolone (16.9% vs. 6.4%; P < 0.001; Table 1).
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Incidence of OTPF
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There were 131 OTPF events in the COPD group during the study period (68,743 patient-
227
years), with an incidence rate of 1.91/1,000 patient-years. In the comparator group matched for
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age, gender, index month, diabetes mellitus, chronic kidney disease and pre-existing
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osteoporosis, there were 429 OTPF events in 278,051 patient-years, with an incidence rate of
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1.54/1,000 patient-years. Patients with COPD were significantly more likely to have OTPF
231
[crude hazard ratio (HR), 1.24; 95% CI, 1.021.51; P = 0.0322; Table 2], as demonstrated by
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separation of the two cumulative incidence curves (Figure 2) and osteoporotic fracture-free
233
survival curves in the KaplanMeier analysis (Supplement Figure 1).
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After multivariate Cox proportional hazards regression controlling for sex, age, vitamin D
235
prescription, insurance premium category, pre-existing osteoporosis and coronary heart disease,
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the difference between the two groups lost statistical significance (aHR, 1.21; 95% CI, 0.992
237
1.469; P = 0.0597). However, when the outcome was a vertebral OTPF, both crude HR (1.33;
238
95% CI, 1.051.69; P = 0.0189) and aHR (1.297; 95% CI, 1.0201.649; P = 0.00339) were
239
statistically significant. Figure 3 demonstrates the clear separation of the two cumulative
240
incidence curves. Owing to few events as long bone fracture, the crude HRs were non-
241
significantly increased, for example, in ulnar fractures and femoral neck fracture (Table 2).
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It is noteworthy that COPD patients who were older (up to 7.5-fold increase of the risk in
243
terms of aHR in patients aged >80 years as compared with the age group of 5059 years), female
244
(3.8-fold increase), who received vitamin D prescriptions (3.3-fold increase), with pre-existing
245
osteoporosis (3-fold increase) or with coronary heart disease (1.5-fold increase) had higher risk
246
for OTPF than their non-COPD comparators (Table 2). In sensitivity analysis based on
247
differential lag time with vertebral OTPF as the outcome, female COPD patients had a sustained
248
and progressively increased risk of vertebral OTPF compared with non-COPD females from the
249
second (aHR = 3.3; 95% CI, 1.895.74; P < 0.0001) to fifth (aHR = 8.0; 95% CI, 1.8135.4; P <
250
0.01) follow-up year. In COPD patients with pre-existing osteoporosis, the risk of vertebral
251
OTPF, approximately 3 to 4-fold increased, sustained through to the fifth follow-up year. COPD
252
patients who were co-prescribed vitamin D had an statistically significantly increased risk in the
253
second (aHR = 3.62; 95% CI, 2.16.23; P < 0.0001) and third (aHR = 2.97; 95% CI, 1.485.97;
254
P < 0.01) follow-up year (Table 3). Comorbidities, such as rheumatoid arthritis, diabetes
255
mellitus, hypertension, dyslipidemia, CKD, liver disease, stroke, or dementia, were not
256
associated with OTPF. In addition, steroid exposure, smoking related diagnoses, alcohol use
257
disorders, and geographic region, were not associated with OTPF (Table 2).
258
259
260
Discussion
We believe this to be the first longitudinal cohort study with a meticulous study design to
261
examine the relationship between COPD and risk of OTPF, particularly vertebral fracture, in an
262
East Asian population. Compared with the comparison cohort matched for age, gender, index
263
month, pre-existing osteoporosis, diabetes mellitus and chronic kidney disease, Asian COPD
264
patients had a significantly increased risk of developing OTPF, with a crude HR of 1.24 (95%
265
CI, 1.021.51). When we examine the OTPF by site, the risk for vertebral fractures in COPD
266
patients increases by approximately 30% even after statistical adjustment for confounding
267
factors. In addition to pre-existing osteoporosis, female gender and those who require vitamin D
268
prescription were important clinical predictors of vertebral OTPF in the COPD population.
269
Chen and colleagues published a retrospective cohort study to examine the risk for
270
osteoporosis in COPD patients in the same region as ours (Chen et al. 2015) Nevertheless, the
271
study reveals some shortcomings: first, pathological fractures resulted from bone metastases,
272
renal osteodystrophy and hyperparathyroidism were not excluded; second, comparators were not
273
matched for pre-existing osteoporosis, diabetes mellitus, and chronic kidney disease; third,
274
vitamin D prescription was not taken into account; and lastly, a half of the COPD cohort aged
275
below 50 years, which are not an optimal population to examine osteoporosis for. Another
276
population-based retrospective cohort study to examine the association between COPD and hip
277
fracture (Huang et al. 2016) revealed that patients with COPD had an approximately 60% greater
278
risk of sustaining hip fracture. Our study cannot confirm this association (crude HR = 2.319;
279
95% CI, 0.687.92; P = 0.1797). Further studies are needed to confirm the potentially existing
280
risk.
281
The prevalence of osteoporosis was significantly higher in COPD patients compared with
282
healthy subjects, with prevalence rates of 9%69% in COPD patients (Graat-Verboom et al.
283
2009). The association between COPD and osteoporosis has been reported in many studies. In a
284
very elderly Chinese male population, COPD was found to be independently associated with low
285
femoral neck bone mineral density (Bian et al. 2015). Higher Global Initiative for Chronic
286
Obstructive Lung Disease (GOLD) stage is reportedly correlated with lower bone mineral
287
density, with every unit decrease in respiratory function (expressed as FEV1 in L/s) associated
288
with a decrease in BMD of approximately 0.02 g/cm2 (Lekamwasam et al. 2002; Lekamwasam
289
et al. 2005; Vrieze et al. 2007). This association was independent of potential confounding
290
factors, such as age, smoking habit, major comorbidity, and medications.
291
However, only a few studies have examined whether patients with COPD have a higher risk
292
of developing OTPF. A recent small cross-sectional study reported by Watanabe and colleagues
293
reveals that the prevalent vertebral fracture is as high as 79.4% in Japanese men with COPD
294
(Watanabe et al. 2015). A case-control study demonstrated an independent association between
295
COPD and increased risk of hip fracture in Catalonians (Reyes et al. 2014). In a multicenter
296
cross-sectional study, Diez-Manglano and colleagues observed a high probability of fracture in
297
347 Spanish COPD inpatients. Overall, nearly half of the COPD patients (95% CI, 44.854.7)
298
had a probability of hip fracture in the next 10 years. The probability of fracture was not related
299
to the GOLD stage. An American retrospective observational study of 87,360 COPD veterans
300
reported a high incidence rate of hip fractures during 4 years of follow-up, with 3.99 events/1000
301
person-years (Morden et al. 2011). However, this study did not include a comparative cohort for
302
the study population. None of the studies mentioned above used a prospective design method. In
303
a further study with a 6-year follow-up of 5,541 males in the general population, patients with
304
COPD or asthma had lower BMD than patients without COPD or asthma, with adjusted odds
305
ratio for vertebral and non-vertebral fractures of 2.6 and 1.4, respectively (odds ratio for presence
306
of COPD or asthma vs. absence of COPD or asthma, 2.64; 95% CI, 1.574.44; and 1.42; 95%
307
CI, 1.031.96, respectively) (Dam et al. 2010). However, the inclusion of patients with asthma
308
limited the ability to evaluate the contribution of COPD to fracture outcomes. Because the
309
abovementioned studies were conducted in the western population and three included men only
310
(Dam et al. 2010; Morden et al. 2011; Reyes et al. 2014), the generalizability to populations in
311
Eastern countries is questionable.
312
The association between COPD and OTPF observed in the present study may be
313
attributable to shared risks between both conditions, such as smoking, physical inactivity, low
314
body weight, and malnutrition (Biskobing 2002; Dam et al. 2010; Jorgensen & Schwarz 2008).
315
Moreover, serum vitamin D levels may also contribute to the risk of OTPF. It has been shown
316
that decreased vitamin D levels were independently associated with increased risk of
317
osteoporosis (defined as vertebral fracture without decreased BMD) by 7.5-fold (Graat-Verboom
318
et al. 2012).
319
It should be noted that OTPF may result from events other than osteoporosis, such as falls.
320
COPD patients typically have many shared risk factors for falls, such as muscle weakness,
321
mobility impairment, and exercise intolerance (Kim et al. 2008; Ries et al. 2007). Compared with
322
healthy controls, the presence of COPD has been shown to be associated with significantly
323
impaired ability to perform balance tests, such as the Berg Balance Scale, timed up and go test,
324
and single-leg stance (Crisan et al. 2015; Porto et al. 2015). An observational cohort study
325
reported a high prevalence of previous falls in COPD patients (32%), with an incidence rate of
326
0.1 (95% CI, 0.060.14) falls/person-month (Roig et al. 2011). In a population-based study,
327
Sibley et al. reported that COPD was significantly associated with increased risk of falls (Sibley
328
et al. 2014). Thus, in addition to osteoporosis, risk factors for falls may play an important role in
329
the correlation between COPD and OTPF. The treatment of such risk factors and osteoporosis is
330
likely required for successful fracture prevention.
331
Patients with CKD are at an increased risk of fragility fracture (Nickolas et al. 2008), which
332
may be explained by CKD-related bone mineral disease and high coprevalence of CKD and
333
osteoporosis in elderly individuals (Klawansky et al. 2003). This is the reason why our study
334
design employed matching the comparison group by this factor.
335
The present study had some clinical implications. According to current guidelines,
336
osteoporosis screening is not recommended for patients with COPD. In the present study, we
337
identified COPD as a potential risk factor for OTPF, particularly vertebral OTPF and the
338
contributing predictors of vertebral OTPF are female COPD patients or those with pre-existing
339
osteoporosis or required vitamin D prescription. Timely arrangement of BMD scanning may
340
increase the possibility of treating osteoporosis and reduce the risk of fracture in this high-risk
341
population. Systemic corticosteroid should be used with cautious as the incidence of fracture
342
increases with duration and dosage of steroid therapy (Canalis et al. 2007; Reid & Heap 1990).
343
Because 87%90% of elderly fractures result from falls (Dargent-Molina et al. 1996; Fife &
344
Barancik 1985), strategies to prevent falls should be implemented in at-risk patients, such as
345
medication review, environmental adjustment, and exercise training. Previous studies have
346
shown that balance training in COPD patients has utility in improving important fall-related
347
factors, such as function, muscle strength, and balance performance (Beauchamp et al. 2013;
348
Harrison et al. 2015). Thus, introducing balance training component into currently existing
349
exercise programs for COPD patients may be of more value in OTPF prevention.
350
Several limitations of the present study have to be acknowledged. First, we were unable to
351
obtain data regarding important fracture risk factors, including BMI, bone marrow density, and
352
calcium intake, family history of OTPF, and physical activity level. Second, the propensity for
353
falls could not be determined because data for risk factors, such as gait abnormality, visual
354
impairment, and living environment, were unavailable. Third, COPD diagnoses were obtained
355
from a claimed dataset, which might not be as accurate as diagnoses made by standardized
356
protocols or tools. However, we excluded outpatients claiming less than two times per year
357
without an inpatient record to increase accuracy. Lastly, the true incidence of prevalent fracture
358
which is existent morphological fracture identified by x-ray during the study period cannot be
359
determined. In the current study, the authors only picked up "clinical fractures" with symptoms
360
because most patients were not taking screening spinal x-ray exams. Thus, upon subject
361
recruitment, a prevalent asymptomatic vertebral fracture can potentially be missed. Similarly, the
362
fracture that this research was looking at was physician-diagnosed clinical fracture identifiable in
363
the national claims database. Thus, the true vertebral fracture incidence during the study period is
364
unknown. Thanks to the nationwide frailty intervention health programs established in Taiwan
365
aiming to reduce the risk of falls and fractures, many if not all asymptomatic pre-clinical
366
vertebral OTPFs have already been screen-detected. The risk of misclassification bias is thus
367
much reduced.
368
The study has several strengths. First, we used compulsory administrative data to identify
369
our study cohorts, which avoids possible volunteer or selection bias. Second, patients in the
370
COPD group of the present study were meticulously matched with individuals without COPD,
371
thereby minimizing possible confounding or bias that may affect other observational studies.
372
Third, the sample of the present study was large and nationwide, increasing the generalizability
373
of the present findings. We believe the effect of the large sample size of the present study may
374
overcome some of the confounding factors caused by minor issues, such as code
375
misclassification and minor differences between the two cohorts or use of medications that effect
376
bone metabolism. Fourth, we excluded patients with fractures that occurred within the first year
377
of COPD diagnosis, which may have been caused by other factors as the time was too short for
378
COPD to have affected bone metabolism.
379
In conclusion, the present large-scale longitudinal study conducted in the Asia-pacific
380
region found an association between OTPF in COPD patients. Among patients with COPD, the
381
risk of fractures was significantly increased in female patients, and those with a diagnosis of
382
osteoporosis, or those who require vitamin D prescription indicating risk for osteoporosis. These
383
results indicate the importance of fall prevention and osteoporosis treatment in patients with
384
COPD. Further prospective cohort studies are required to confirm the causal relationship
385
between COPD and OTPF.
386
387
388
Acknowledgements
389
The authors wish to thank the Administration of the National Health Insurance and the National
390
Health Research Institute, Taiwan, for the dataset used to conduct this research. The
391
interpretation and conclusions contained herein do not represent those of the institutions above.
392
393
References
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
Abrahamsen B, van Staa T, Ariely R, Olson M, and Cooper C. 2009. Excess mortality following
hip fracture: a systematic epidemiological review. Osteoporos Int 20:1633-1650.
10.1007/s00198-009-0920-3
Beauchamp MK, Janaudis-Ferreira T, Parreira V, Romano JM, Woon L, Goldstein RS, and Brooks
D. 2013. A randomized controlled trial of balance training during pulmonary
rehabilitation for individuals with COPD. Chest 144:1803-1810. 10.1378/chest.13-1093
Bian P, Li X, Ying Q, Chen J, Jin X, Yao J, and Shou Z. 2015. Factors associated with low femoral
neck bone mineral density in very elderly Chinese males. Arch Gerontol Geriatr 61:484488. 10.1016/j.archger.2015.08.010
Biskobing DM. 2002. COPD and osteoporosis. Chest 121:609-620.
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, and Tosteson A. 2007. Incidence and
economic burden of osteoporosis-related fractures in the United States, 2005-2025. J
Bone Miner Res 22:465-475. 10.1359/jbmr.061113
Canalis E, Mazziotti G, Giustina A, and Bilezikian JP. 2007. Glucocorticoid-induced osteoporosis:
pathophysiology and therapy. Osteoporos Int 18:1319-1328. 10.1007/s00198-007-03940
Chen SJ, Liao WC, Huang KH, Lin CL, Tsai WC, Kung PT, Chang KH, and Kao CH. 2015. Chronic
obstructive pulmonary disease and allied conditions is a strong independent risk factor
for osteoporosis and pathologic fractures: a population-based cohort study. Qjm
108:633-640. 10.1093/qjmed/hcv012
Choi YJ, Oh HJ, Kim DJ, Lee Y, and Chung YS. 2012. The prevalence of osteoporosis in Korean
adults aged 50 years or older and the higher diagnosis rates in women who were
beneficiaries of a national screening program: the Korea National Health and Nutrition
Examination Survey 2008-2009. J Bone Miner Res 27:1879-1886. 10.1002/jbmr.1635
Crisan AF, Oancea C, Timar B, Fira-Mladinescu O, and Tudorache V. 2015. Balance impairment
in patients with COPD. PLoS One 10:e0120573. 10.1371/journal.pone.0120573
Dam TT, Harrison S, Fink HA, Ramsdell J, and Barrett-Connor E. 2010. Bone mineral density and
fractures in older men with chronic obstructive pulmonary disease or asthma.
Osteoporos Int 21:1341-1349. 10.1007/s00198-009-1076-x
Dargent-Molina P, Favier F, Grandjean H, Baudoin C, Schott AM, Hausherr E, Meunier PJ, and
Breart G. 1996. Fall-related factors and risk of hip fracture: the EPIDOS prospective
study. Lancet 348:145-149.
Eisler J, Cornwall R, Strauss E, Koval K, Siu A, and Gilbert M. 2002. Outcomes of elderly patients
with nondisplaced femoral neck fractures. Clin Orthop Relat Res:52-58.
Fife D, and Barancik JI. 1985. Northeastern Ohio Trauma Study III: incidence of fractures. Ann
Emerg Med 14:244-248.
Graat-Verboom L, Smeenk FW, van den Borne BE, Spruit MA, Jansen FH, van Enschot JW, and
Wouters EF. 2012. Progression of osteoporosis in patients with COPD: a 3-year follow up
study. Respir Med 106:861-870. 10.1016/j.rmed.2011.12.020
Graat-Verboom L, Wouters EF, Smeenk FW, van den Borne BE, Lunde R, and Spruit MA. 2009.
Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J
34:209-218. 10.1183/09031936.50130408
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
Harrison SL, Beauchamp MK, Sibley K, Araujo T, Romano J, Goldstein RS, and Brooks D. 2015.
Minimizing the evidence-practice gap - a prospective cohort study incorporating balance
training into pulmonary rehabilitation for individuals with chronic obstructive
pulmonary disease. BMC Pulm Med 15:73. 10.1186/s12890-015-0067-2
Huang SW, Wang WT, Chou LC, Chen HC, Liou TH, and Lin HW. 2016. Chronic Obstructive
Pulmonary Disease Increases the Risk of Hip Fracture: A Nationwide Population-Based
Cohort Study. Sci Rep 6:23360. 10.1038/srep23360
Iki M, Kagamimori S, Kagawa Y, Matsuzaki T, Yoneshima H, and Marumo F. 2001. Bone mineral
density of the spine, hip and distal forearm in representative samples of the Japanese
female population: Japanese Population-Based Osteoporosis (JPOS) Study. Osteoporos
Int 12:529-537. 10.1007/s001980170073
Jaramillo JD, Wilson C, Stinson DS, Lynch DA, Bowler RP, Lutz S, Bon JM, Arnold B, McDonald
ML, Washko GR, Wan ES, DeMeo DL, Foreman MG, Soler X, Lindsay SE, Lane NE, Genant
HK, Silverman EK, Hokanson JE, Make BJ, Crapo JD, and Regan EA. 2015. Reduced Bone
Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk.
Ann Am Thorac Soc 12:648-656. 10.1513/AnnalsATS.201412-591OC
Johnell O, and Kanis JA. 2006. An estimate of the worldwide prevalence and disability
associated with osteoporotic fractures. Osteoporos Int 17:1726-1733. 10.1007/s00198006-0172-4
Jorgensen NR, and Schwarz P. 2008. Osteoporosis in chronic obstructive pulmonary disease
patients. Curr Opin Pulm Med 14:122-127. 10.1097/MCP.0b013e3282f4efb6
Kim HC, Mofarrahi M, and Hussain SN. 2008. Skeletal muscle dysfunction in patients with
chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 3:637-658.
Klawansky S, Komaroff E, Cavanaugh PF, Jr., Mitchell DY, Gordon MJ, Connelly JE, and Ross SD.
2003. Relationship between age, renal function and bone mineral density in the US
population. Osteoporos Int 14:570-576. 10.1007/s00198-003-1435-y
Kok VC, Horng JT, Chang WS, Hong YF, and Chang TH. 2014. Allopurinol therapy in gout patients
does not associate with beneficial cardiovascular outcomes: a population-based
matched-cohort study. PLoS One 9:e99102. 10.1371/journal.pone.0099102
Kok VC, Horng JT, Hung GD, Xu JL, Hung TW, Chen YC, and Chen CL. 2016. Risk of Autoimmune
Disease in Adults with Chronic Insomnia Requiring Sleep-Inducing Pills: A PopulationBased Longitudinal Study. J Gen Intern Med. 10.1007/s11606-016-3717-z
Kok VC, Sung FC, Kao CH, Lin CC, and Tseng CH. 2015a. Cancer risk in East Asian patients
associated with acquired haemolytic anaemia: a nationwide population-based cohort
study. BMC Cancer 16:57. 10.1186/s12885-016-2098-3
Kok VC, Tsai HJ, Su CF, and Lee CK. 2015b. The Risks for Ovarian, Endometrial, Breast,
Colorectal, and Other Cancers in Women With Newly Diagnosed Endometriosis or
Adenomyosis: A Population-Based Study. Int J Gynecol Cancer 25:968-976.
10.1097/IGC.0000000000000454
Kulak CA, Borba VC, Jorgetti V, Dos Reis LM, Liu XS, Kimmel DB, Kulak J, Jr., Rabelo LM, Zhou H,
Guo XE, Bilezikian JP, Boguszewski CL, and Dempster DW. 2010. Skeletal microstructural
abnormalities in postmenopausal women with chronic obstructive pulmonary disease. J
Bone Miner Res 25:1931-1940. 10.1002/jbmr.88
Lekamwasam S, Trivedi DP, and Khaw KT. 2002. An association between respiratory function
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
and bone mineral density in women from the general community: a cross sectional
study. Osteoporos Int 13:710-715. 10.1007/s001980200097
Lekamwasam S, Trivedi DP, and Khaw KT. 2005. An association between respiratory function
and hip bone mineral density in older men: a cross-sectional study. Osteoporos Int
16:204-207. 10.1007/s00198-004-1673-7
Looker AC. 2014. Relationship between femur neck bone mineral density and prevalent chronic
obstructive pulmonary disease (COPD) or COPD mortality in older non-Hispanic white
adults from NHANES III. Osteoporos Int 25:1043-1052. 10.1007/s00198-013-2601-5
Morden NE, Sullivan SD, Bartle B, and Lee TA. 2011. Skeletal health in men with chronic lung
disease: rates of testing, treatment, and fractures. Osteoporos Int 22:1855-1862.
10.1007/s00198-010-1423-y
Nelson HD, Haney EM, Dana T, Bougatsos C, and Chou R. 2010. Screening for osteoporosis: an
update for the U.S. Preventive Services Task Force. Ann Intern Med 153:99-111.
10.7326/0003-4819-153-2-201007200-00262
Nickolas TL, Leonard MB, and Shane E. 2008. Chronic kidney disease and bone fracture: a
growing concern. Kidney Int 74:721-731. 10.1038/ki.2008.264
Ogura-Tomomatsu H, Asano K, Tomomatsu K, Miyata J, Ohmori N, Kodama M, Ueda S, Takihara
T, Tanaka K, Kamiishi N, Suzuki Y, Fukunaga K, Oguma T, Sayama K, and Betsuyaku T.
2012. Predictors of osteoporosis and vertebral fractures in patients presenting with
moderate-to-severe chronic obstructive lung disease. Copd 9:332-337.
10.3109/15412555.2012.667850
Poole KE, and Compston JE. 2006. Osteoporosis and its management. BMJ 333:1251-1256.
333/7581/1251 [pii]
10.1136/bmj.39050.597350.47
Porto EF, Castro AA, Schmidt VG, Rabelo HM, Kumpel C, Nascimento OA, and Jardim JR. 2015.
Postural control in chronic obstructive pulmonary disease: a systematic review. Int J
Chron Obstruct Pulmon Dis 10:1233-1239. 10.2147/COPD.S63955
Reid IR, and Heap SW. 1990. Determinants of vertebral mineral density in patients receiving
long-term glucocorticoid therapy. Arch Intern Med 150:2545-2548.
Reyes C, Estrada P, Nogues X, Orozco P, Cooper C, Diez-Perez A, Formiga F, Gonzalez-Macias J,
and Prieto-Alhambra D. 2014. The impact of common co-morbidities (as measured using
the Charlson index) on hip fracture risk in elderly men: a population-based cohort study.
Osteoporos Int 25:1751-1758. 10.1007/s00198-014-2682-9
Ries AL, Bauldoff GS, Carlin BW, Casaburi R, Emery CF, Mahler DA, Make B, Rochester CL,
Zuwallack R, and Herrerias C. 2007. Pulmonary Rehabilitation: Joint ACCP/AACVPR
Evidence-Based Clinical Practice Guidelines. Chest 131:4S-42S. 10.1378/chest.06-2418
Roig M, Eng JJ, MacIntyre DL, Road JD, FitzGerald JM, Burns J, and Reid WD. 2011. Falls in
people with chronic obstructive pulmonary disease: an observational cohort study.
Respir Med 105:461-469. 10.1016/j.rmed.2010.08.015
Schnell K, Weiss CO, Lee T, Krishnan JA, Leff B, Wolff JL, and Boyd C. 2012. The prevalence of
clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: a
cross-sectional study using data from NHANES 1999-2008. BMC Pulm Med 12:26.
10.1186/1471-2466-12-26
Schuit SC, van der Klift M, Weel AE, de Laet CE, Burger H, Seeman E, Hofman A, Uitterlinden AG,
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
van Leeuwen JP, and Pols HA. 2004. Fracture incidence and association with bone
mineral density in elderly men and women: the Rotterdam Study. Bone 34:195-202.
Sibley KM, Voth J, Munce SE, Straus SE, and Jaglal SB. 2014. Chronic disease and falls in
community-dwelling Canadians over 65 years old: a population-based study exploring
associations with number and pattern of chronic conditions. BMC Geriatr 14:22.
10.1186/1471-2318-14-22
Vrieze A, de Greef MH, Wijkstra PJ, and Wempe JB. 2007. Low bone mineral density in COPD
patients related to worse lung function, low weight and decreased fat-free mass.
Osteoporos Int 18:1197-1202. 10.1007/s00198-007-0355-7
Watanabe R, Tanaka T, Aita K, Hagiya M, Homma T, Yokosuka K, Yamakawa H, Yarita T, Tai N,
Hirano J, Inoue D, and Okazaki R. 2015. Osteoporosis is highly prevalent in Japanese
males with chronic obstructive pulmonary disease and is associated with deteriorated
pulmonary function. J Bone Miner Metab 33:392-400. 10.1007/s00774-014-0605-7
Wu XP, Liao EY, Zhang H, Dai RC, Shan PF, Cao XZ, Liu SP, and Jiang Y. 2004. Determination of
age-specific bone mineral density and comparison of diagnosis and prevalence of
primary osteoporosis in Chinese women based on both Chinese and World Health
Organization criteria. J Bone Miner Metab 22:382-391. 10.1007/s00774-004-0499-x
542
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Figure legends
544
545
Figure 1. Consort diagram of the present study flow.
546
547
Figure 2. Cumulative incidence curves of osteoporotic fracture in COPD patients and non-COPD
548
comparators matched for age, sex, index date, pre-existing osteoporosis, diabetes mellitus and
549
chronic kidney disease.
550
551
Figure 3. Cumulative incidence curves of osteoporotic vertebral fracture in COPD patients and
552
non-COPD comparators after multivariate adjustment.
553
554
Supplement Figure 1. Kaplan-Meier fracture-free survival curves of COPD patients and non-
555
COPD comparators matched for age, sex, index date, pre-existing osteoporosis, diabetes mellitus
556
and chronic kidney disease.
Figure 1
Consort diagram of the present study flow.
Figure 2
Cumulative incidence curves of osteoporotic fracture in COPD patients and non-COPD
comparators matched for age, sex, index date, osteoporosis, diabetes mellitus and
chronic kidney disease.
Figure 3
Cumulative incidence curves of osteoporotic vertebral fracture in COPD patients and
non-COPD comparators after multivariate adjustment.
Table 1(on next page)
Demographic characteristics of COPD patients and Non-COPD patients 1-to-4-matched
by age, sex, index date, diabetes mellitus, pre-existing osteoporosis, and chronic kidney
disease.
1
2
Table 1. Demographic characteristics of COPD patients and Non-COPD patients 1-to-4-matched

by age, sex, index date, diabetes mellitus, pre-existing osteoporosis, and chronic kidney disease.
Descriptor
COPD patients
Non-COPD patients
N = 19,740
Age mean (SD)
(%)
66.02 (10.23)
Age group
N = 78,960
P value
(%)
65.92 (10.23)
50 ~ 59
6423
32.54
26140
33.11
60 ~ 69
5915
29.96
23501
29.76
70 ~ 79
5077
25.72
20215
25.60
>80
2325
11.78
9104
11.53
Gender
Female
8732
44.24
34928
44.24
11008
55.76
44032
55.76
Diabetes mellitus
4726
23.94
18904
23.94
Osteoporosis
1187
6.01
4748
6.01
Chronic kidney disease
2746
13.91
10984
13.91
Male
Other matched characteristics
Follow-up (Year) / Mean (SD)
2.97 (2.06)
3.01 (2.05)
0.0949
3051
15.46
11618
14.71
2976
15.08
11707
14.83
2820
14.29
11355
14.38
2575
13.04
10442
13.22
2523
12.78
10309
13.06
2597
13.16
10754
13.62
3170
16.06
12691
16.07
Residential Area
<0.0001
North
8386
42.48
34410
43.58
Central
5300
26.85
19132
24.23
South
5330
27.00
22655
28.69
591
2.99
1934
2.45
12353
62.58
2772
3.51
<0.0001
598
3.03
1557
1.97
<0.0001
East
Smoking-related Diagnoses
Alcohol use disorder
Insurance Premium Category
<0.0001
<15,000 NTD
10041
50.87
39186
49.63
15,00021,999 NTD
6028
30.54
23634
29.93
22,000 NTD
3671
18.60
16140
20.44
545
2.76
1790
2.27
<0.0001
Hypertension
11509
58.30
44266
56.06
<0.0001
Dyslipidemia
6813
34.51
27511
34.84
0.3868
Coronary heart disease
5528
28.00
17192
21.77
<0.0001
Liver disease
3824
19.37
13644
19.28
<0.0001
Stroke
3994
20.23
12188
15.44
<0.0001
Dementia
1144
5.80
2481
3.14
<0.0001
1214
6.17
440
0.56
<0.0001
267
1.36
169
0.21
<0.0001
Ciclesonide
46
0.23
16
0.02
<0.0001
Fluticasone
1762
8.96
425
0.54
<0.0001
Cortisone acetate
62
0.32
125
0.16
<0.0001
Dexamethasone
325
1.65
770
0.98
<0.0001
Fludrocortisone
18
0.09
51
0.06
<0.0001
373
1.90
656
0.83
<0.0001
3330
16.93
5012
6.36
<0.0001
30
0.15
97
0.12
<0.0001
487
2.48
1689
2.14
0.0045
Comorbidities
Rheumatoid Arthritis
Type of ICS
Budesonide
Beclomethasone
Type of OCS
Methylprednisolone
Prednisolone
Triamcinolone
Vitamin D prescription
CCI score / Mean (SD)
3
4
5
6
1.14 (1.36)
1.02 (1.32)
<0.0001
CCI score 0
8604
43.59
38699
49.01
CCI score 1, 2
8051
40.79
29345
37.16
CCI score 3, 4
2308
11.69
8235
10.43
CCI score 5
777
3.94
2681
3.40
*COPD was excluded from the CCI score in the COPD cohort.
CCI: Charlson-Deyo comorbidity index; ICS: inhaled corticosteroid; NTD: New Taiwan Dollar; OCS: oral
corticosteroid; SD: standard deviation
Incidence of osteoporotic fractures for COPD patients compared with non-COPD patients
and crude and adjusted hazard ratio for an episode of osteoporotic fracture
1
2
3
4
Table 2. Incidence of osteoporotic fractures for COPD patients compared with non-COPD
patients and crude and adjusted hazard ratio for an episode of osteoporotic fracture
Variables
COPD patients
Event
All
PY
Non-COPD patients
Rate
Event
PY
Rate
Incidence Rate Ratio

(95 % CI)
Crude HR
Adjusted HR*
1.24 (1.02 1.51)

(P =0.0322)
1.33 (1.05 1.69)
(P =0.0189)
1.35 (0.14 12.99)
(P =0.7943)
1.207 (0.992 1.469

(P =0.0597)
1.297 (1.020 1.649)
(P =0.0339)
131
68743.3
1.91
429 278050.7
1.54
1.24 (1.011.51)
89
68743.3
1.29
271 278050.7
0.97
1.33 (1.031.69)
68743.3
0.01
3 278050.7
0.01
1.35 (0.0316.79)
68743.3
0.06
7 278050.7
0.03
2.31 (0.509.09)
2.319 (0.68 7.92)

(P =0.1797)
50-59
10
23495.89
0.43
22 96405.22
0.23
1.87 (0.794.10)
60-69
29
20797.03
1.39
94 83199.61
1.13
1.23 (0.781.89)
3.30 (1.61 6.77)

(P =0.0011)
70-79
62
17398.42
3.56
188
69866.2
2.69
1.32 (0.981.77)
8.44 (4.33 16.46)

(P <0.0001)
>80
30
7051.96
4.25
125 28579.67
4.37
0.97 (0.631.46)
10.33 (5.05 21.13)

(P <0.0001)
2.462 (1.16 5.222)

(P =0.0189)
7.124 (3.395
14.951)
(P <0.0001)
7.482 (3.299
16.971)
(P <0.0001)
23 37817.02
0.61
152742
0.37
1.63 (0.962.69)
108 30926.28
3.49
372 125308.8
2.97
1.18 (0.941.46)
5.70 (3.64 8.95)

(P <0.0001)
3.817 (2.388 6.1)

(P <0.0001)
Vertebral fractures
Ulna fractures
Neck of femur
fractures
Age
Sex
Male
Female
57
Vitamin D prescription
No
108 66601.18
Yes
23
1.62
2142.12
10.74
92 41622.03
2.21
380 270804.9
1.4
1.16 (0.921.43)
7245.82
6.76
1.59 (0.922.66)
6.375 (4.06 10.00)

(P <0.0001)
3.3 (2.08 5.236)

(P <0.0001)
364 219780.6
1.66
1.33 (1.051.68)
49
Steroid exposure
No steroid
ICS regular use
2768.1
0.36
688.57
1.45
0.25 (0.00319.53)
0.154 (0.022-1.107)
(P = 0.0631)
OCS regular use
1097.32
0.91
2294.96
0.44
2.09 (0.03164.17)
0.391 (0.055-2.807)
(P =0.3506)
No
56
26518.7
2.11
419 269633.1
1.55
1.36 (1.011.80)
Yes
75
42224.6
1.78
8417.64
1.19
1.50 (0.773.24)
131 67001.73
1.96
429 273623.2
1.57
1.25 (1.021.52)
4427.45
NA
NA
NA
257 135747.5
0.99
0.99 (0.741.31)
Smoking-related
diagnoses
10
0.848 (0.6 1.20)

(P =0.3497)
Alcohol use disorders

No
Yes
1741.57
NA
64
34007.32
1.88
Insurance premium
(NTD)
<15,000
60 21653.09
2.77
158 84330.74
1.87
1.48 (1.082.00)
3.56 (1.63 - 7.76)

(P =0.0014)
1.394 (0.583 - 3.335)

(P =0.4554)
7 13082.89
0.54
14 57972.41
0.24
2.22 (0.765.87)
5.18 (2.37 - 11.33)

(P <0.0001)
1.171 (0.472 2.901)

(P =0.7338)
North
54 29259.38
1.85
175 121378.3
1.44
1.28 (0.931.75)
Central
45
18457
2.44
141 66933.68
2.11
1.16 (0.811.63)
1.32 (0.89 - 1.97)

(P =0.1658)
South
29 18390.64
1.58
101 79909.28
1.26
1.25 (0.801.91)
0.856(0.55 - 1.35)
(P =0.50)
6843.38
1.02
1.38 (0.236.03)
0.76 (0.23 - 2.43)

(P =0.6414)
407 272383.3
1.49
1.29 (1.051.57)
5667.4
3.88
0.31 (0.041.27)
0.651 (0.161 2.629)

(P =0.5463)
15,00021,999
22,000
Geographic area
East
2130.77
1.41
129 67096.49
1.92
Comorbidities
Rheumatoid Arthritis
No
Yes
1646.81
1.21
22
No
102 53458.33
1.91
349 216876.3
1.61
1.19 (0.941.48)
Yes
29 15284.97
1.9
80 61174.37
1.31
1.45 (0.912.24)
1.015 (0.672 1.533)

(P =0.9449)
52 29753.16
1.75
149 128167.5
1.16
1.50 (1.072.07)
Diabetes mellitus
Hypertension
No
79 38990.13
2.03
280 149883.2
1.87
1.08 (0.831.40)
1.176 (0.829 1.669)

(P =0.3646)
No
81 46397.68
1.75
287 188947.6
1.52
1.15 (0.891.48)
Yes
50 22345.62
2.24
142 89103.05
1.59
1.40 (1.001.95)
1.305 (0.917 1.858)

(P =0.1386)
No
93 65071.05
1.43
297 262971.8
1.13
1.27 (0.991.60)
Yes
38
3672.25
10.35
132 15078.89
8.75
1.18 (0.801.71)
No
75
50255.5
1.49
299 222287.6
1.35
1.11 (0.851.43)
Yes
56 18487.79
3.03
130 55763.07
2.33
1.30 (0.931.79)
2.05 (1.45 2.899)

(P <0.0001)
1.471 (1.037 2.088)

(P =0.0306)
113 60552.14
2.24
375
245400
1.83
1.22 (0.981.51)
Yes
Dyslipidemia
Osteoporosis
1
7.399 (5.071 10.796) 3.01 (2.019 4.487)

(P <0. 0001)
(P <0. 0001)
Coronary heart
disease
Chronic kidney
disease
No
Yes
8191.16
2.2
54 32650.65
1.65
1.33 (0.732.30)
1.222 (0.743 2.010)

(P =0.4303)
109 56439.49
1.93
352 235095.9
1.5
1.29 (1.031.60)
18
Liver disease
No
Yes
22 12303.81
1.79
77 42954.81
1.79
1.0 (0.591.62)
0.944 (0.597 1.493)

(P =0.8051)
No
111 56270.64
1.97
343 238988.5
1.44
1.37 (1.101.71)
Yes
20 12472.65
1.6
86 39062.17
2.2
0.73 (0.421.20)
0.834 (0.518 1.344)

(P =0.456)
125 65485.98
1.91
408 270683.4
1.51
1.26 (1.031.55)
2.85
0.65 (0.211.66)
1.003 (0.442 2.277)

(P =0.9934)
Stroke
Dementia
No
Yes
5
6
7
8
3257.32
1.84
21
7367.3
Hazard ratio calculation: For fracture sites, comparison was made between COPD and nonCOPD; in subcategories such as age and sex, HR is based on the comparison among
subcategories with the reference group.
9
10
11
12
13
14
Event = Number of Osteoporotic Fractures; PY = Person Years; Rate = Incidence per 1,000 PY;
CKD = Chronic kidney disease; HR = Hazard Ratio; ICS = inhaled corticosteroids; IHD = Ischemic
heart disease; NA = not applicable; OCS = oral corticosteroids.
*Multivariate Cox regression model derived HR was adjusted for sex, age group, vitamin D
prescription, insurance premium category, pre-existing osteoporosis and coronary heart
disease.
15
16
17
Only regular users by pre-determined definitions were included for analysis.

Bold type numerals denote statistical significance.
Sensitivity Analysis.
Table 3. Sensitivity analysis showing the effect of differential time lag on the risk of
osteoporotic fractures among COPD patients who possessed the characteristic
1
2
3
4
Table 3. Sensitivity analysis showing the effect of differential time lag on the risk of osteoporotic vertebral fractures among COPD
patients who possessed the contributing characteristics.
2nd follow up year
Predictive Variable
Female
Osteoporosis
Vitamin D
Prescription
Coronary Heart
Disease
5
6
7
8
x/y
7439/
9222
959/
15702
aHR (95%
A/B
CI)
3.3(1.895.74)****
3.31(2.0427/62
5.35)****
72/17
3rd follow up year

x/y
A/B
aHR (95%
CI)
4th follow up year

x/y
A/B
aHR (95%
CI)
5th follow up year

x/y
A/B
6177/
3.48(1.75- 4909/
4.46(1.81- 3762/
48/11
31/6
20/2
6.9)*** 5956
11.03)** 4528
7508
758/
3.35(1.84- 568/
3.51(1.64- 393/
17/42
10/27
7/15
6.09)**** 10297
7.51)** 7897
12927
468/
16193
17/72
3.62(2.1- 419/
2.97(1.48- 360/
1.69(0.59- 295/
10/49
4/33
6.23)**** 13266
5.97)** 10505
4.87)
7995
4590/
12071
38/51
1.45(0.95- 3724/
1.39(0.82- 2913/
1.04(0.52- 2148/
24/35
12/25
7/15
2.22)
9961
2.34)
7952
2.09)
6142
3/19
aHR (95%
CI)
6th follow up year

x/y
8.0(1.81- 2623/
35.4)**
3144
4.08(1.61- 253/
10.35)** 5514
1.9(0.556.57)
A/B
8/0
2/6
aHR (95%
CI)
x/y
1444/
1726
2.45(0.48- 125/
12.41)
3045
-
A/B
2/0
1/1
212/
5555
2/6
4.48(0.8822.9)
116/
3054
1/1
0.97(0.39- 1437/
2.41)
4330
2/6
0.69(0.143.47)
764/
2406
0/2
Bold type numerals denote achieving statistically significant. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001
x/y: number of patients at risk with the characteristic/number of patients at risk without the characteristic.
A/B: number of patients who developed osteoporotic fracture in X/number of patients who developed osteoporotic fracture in Y.
The Cox model was adjusted for sex, age group, vitamin D prescription, and pre-existing osteoporosis.
7th follow up

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Manuscript to be reviewed

Risk and clinical predictors of osteoporotic fracture in East

Department of Geriatric Medicine, Kuang Tien General Hospital, Taichung, Taiwan

Corresponding Authors: Victor C Kok, Jorng-Tzong Horng

Introduction: Osteoporosis is becoming an impending epidemic in the Asia-Pacific region. The

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

Risk and clinical predictors of osteoporotic fracture in East Asian

patients with chronic obstructive pulmonary disease: a population-

based cohort study

Short Title: Osteoporotic fracture in Asians with COPD

Chang Ku2, 7, MD; Yu-Ching Chen3, 5, PhD; Jorng-Tzong Horng3, 5, 6, *, PhD.

of Internal Medicine, Kuang Tien General Hospital, Taichung, Taiwan

of Geriatric Medicine, Kuang Tien General Hospital, Taichung, Taiwan

Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan

Victor C. Kok, MMedSc, MD, PhD, FACP

Kuang Tien General Hospital

117 Shatien Road Shalu, Taichung 43303, Taiwan

Tel: +886 4 26625111, ext: 2263

Fax: +886 4 26655050

Jorng-Tzong Horng, PhD

Department of Computer Science and Information Engineering

National Central University

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

300 Jhongda Road, Jhongli, Taoyuan 32001, Taiwan

Tel +886 919 057 555

Tables: 4 (including one supplement table)

Figures: 4 (including one supplement figure)

Word count of the main manuscript: 3717

Abstract word count: 413

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

Introduction: Osteoporosis is becoming an impending epidemic in the Asia-Pacific region. The

disease (COPD) in East Asian patients is yet to be fully examined.

We conducted a nationwide population-based retrospective cohort study of 98,700 patients aged

50 years with or without COPD using a national administrative claims dataset.

inhaled corticosteroids and oral corticosteroids, vitamin D prescriptions, Charlson-Deyo

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

(Word count: 413)

Keywords: COPD, osteoporotic fracture, Asian, longitudinal study, osteoporosis

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

estimated to increase to $25.3 billion by 2025 (Burge et al. 2007).

sufficient to detect high-risk patients in a timely and cost-effective manner (Ogura-Tomomatsu et

al. 2012; Schuit et al. 2004).

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

contributed by clinical predictors would be calculated.

Materials and Methods

Insurance (NHI) program, established in 1995 in Taiwan, is a mandatory health insurance

was required for this study.

We conducted a population-based, observational, cohort study to assess the association

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

medical comorbidities including diabetes mellitus, pre-existing osteoporosis, chronic kidney

(ICS: budesonide, beclomethasone, ciclesonide, fluticasone) and oral corticosteroids (OCS:

cortisone acetate, dexamethasone, fludrocortisone, methylprednisolone, prednisolone,

metastases (ICD-9-CM code 198.5), renal osteodystrophy (588.0) and secondary

fracture due to osteoporosis (ICD-9-CM codes: 733.0x + 733.1x) documented in inpatient or

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

that resulted from cancer metastasis, renal osteodystrophy, or secondary hyperparathyroidism

Covariates and confounders

Socioeconomic status of participating subjects was approximated using different category

patient was collected.

PeerJ reviewing PDF | (2016:06:11532:2:0:NEW 29 Sep 2016)

Statistics Version 22).

Characteristics of the study population

Except for dyslipidemia, all non-matching co-morbidities, such as rheumatoid arthritis,